The autoimmune diseases, such as Rheumatoid arthritis (RA), Systemic lupus erythematosus (SLE), Sjögren's syndrome (sjogren syndrome) and so on, are closely related to the excessive proliferation of B cell or plasmocyte of the body and humoral immune activation.
B cell activating factor (BAFF), also known as BLyS, TALL-1, THANK, zTNF4 or TNFSF-13B, which is a member of the TNF family, which was discovered in 1999[1], initiates downstream signaling pathways and regulates of B cell's survival, maturation and differentiation[2] by binding to its homologous receptors. BAFF and other three ligands (APRIL, EDA and TWEAK) belong to the same subtype, and have the similar function and structure characteristics[3]. BAFF, which has membrane-bound and soluble forms, is a type II transmembrane protein. The soluble form is composed of 152 amino acids, and is produced following proteolysis of the membrane-bound form (which has 285 amino acids) between R133 and A134 by proteases. This process is regulated at both a stimulus and cell type level[3]. Under normal physiological conditions, soluble BAFF exists as a trimer and expresses the biological activity[4]. BAFF is mainly produced by peripheral blood mononuclear cells (PBMNCs), including the macrophages, monocytes and dendritic cells in the spleen and lymph nodes[5].
The three receptors of BAFF: BCMA (B cell maturation antigen), TACI (transmembrane activator and CAML interactor) and BAFF-R (BAFF receptor, Br3), which is disclosed in prior art are all type III transmembrane protein. BAFF and APRIL are capable of binding to TACI and BCMA with high affinity, and BAFF can also bind to BAFF-R. Extracellular domain of TNF receptor contains multiple cysteine-rich domains (CRD), and each CRD is comprised of three disulfide bonds which are formed by six cysteine residues. BCMA has single CRD, and compared to BCMA, TACI contains two typical CRD: CRD1 and CRD2, wherein only CRD2 involves ligand binding (TACI (aa.70-104): see SEQ ID NO:8)[6]. Br3 contains only one CRD which consists of 4 cysteine residues (Br3 (aa.18-35): see SEQ ID NO:9), and binding domain to BAFF is reduced to 26 amino acids[7].
Besides the function of promoting B cell survival, BAFF also plays an important role of regulation in the maintenance of the germinal center reaction, isotype switching, T cell activation and so on. BAFF has the effect on T cell activation, so it may play an important role in pathogenesis of autoimmune diseases. Therefore, BAFF and its receptors as novel targets for treatment of autoimmune diseases have received wide concern. The specific antagonist of BATF (including soluble receptor TACI-Fc, Br3-Fc or anti-BAFF antibodies and so on) can inhibit the biological activity of BAFF, thereby playing a role in the treatment of autoimmune disease, such as rheumatoid arthritis (RA), Sjögren's syndrome, systemic lupus erythematosus (SLE) and so on. At present, in March 2011, FDA had approved fully human anti-BAFF monoclonal antibody Belimumab (trade name: Benlysta) listed, indications for SLE, which become the first listed new drugs for treating lupus in more than 50 years, and the treatment for RA has also entered into clinical trial phase III; research on soluble receptor TACI-Fc treating SLE and RA has already entered into phase II/III clinical trial.